reverse transcriptase inhibitors in ags

Conditions: Aicardi-Goutières Syndrome (AGS)

Summary: the purpose of this study is to determine if treatment with reverse transcriptase inhibitors returns the interferon signature observed in patients with ags to normal levels.

ags is a genetically heterogeneous disease resulting from mutations in any one of the genes encoding the 3-prime repair exonuclease trex1 (ags1), the three non-allelic components of the rnaseh2 endonuclease complex (ags2, 3 and 4), the sam domain and hd domain containing protein (samhd1; ags5) which functions as a deoxynucleoside triphosphate triphosphohydrolase, the double stranded rna editing enzyme adar1, or the cytosolic dsrna sensor ifih1. it is hypothesized that ags1-6 are involved in limiting the accumulation of intracellular nucleic acid species, a failure of which process results in triggering of an innate immune response that is more normally induced by viral nucleic acids. that is, in the absence of ags-related protein activity, endogenous nucleic acids accumulate and are sensed as viral or 'non-self', leading to the induction of an interferon (ifn) alpha mediated immune response and the production of antibodies against self nucleic acids. ags is associated with increased levels of interferon alpha in the cerebrospinal fluid (csf) and serum. available data suggest that ags might be treated with (particular) reverse transcriptase inhibitors (which compounds can potentially disrupt both exogenous retroviral and endogenous retroelement cycling). no systematic approach to treatment in ags has been explored. the investigators hypothesis is that reverse transcriptase inhibitors will also inhibit the reverse transcription of endogenous retroelements which are deemed to be responsible for initiating the tissue damage seen in ags. consequently, for the purpose of the investigators pilot study, it would be ideal to assess the effects of therapy by monitoring a reactive biomarker. this is a single centre, open, single arm, phase ii study in children with ags. this study design is justified because no data are available about antiretroviral drug efficacy in children with ags. moreover, this study is the first step before a phase iii study of drug efficacy. the investigators propose a pilot clinical trial of selected reverse transcriptase inhibitors in ags patients, with the specific endpoint of assessing the effect of treatment on the disease-associated interferon signature. the investigators propose to evaluate the safety of combination therapy comprising the three nucleoside analog reverse-transcriptase inhibitors (nrtis) zidovudine (azt), lamivudine (3tc), abacavir (abc) in patients with ags over a 52 week period of treatment. the inclusion period is 12 months. patients can not participate in a biomedical trial of another drug during the 18 month follow-up (12 months of treatment period plus 6 months post treatment period). a total of six visits (including a final visit) are scheduled for this trial over a period of 18 months (m1, m3, m6, m9, m12, m18) for all patients. drugs will be dispensed for medication at home, at usual doses recommended in hiv infection. subjects will be dosed according to french guidelines. dosing will be reviewed at each study visit against current weight, and modified as necessary in accordance with french dosing guidelines.

Eligibility criteria:
inclusion criteria: * a molecular diagnosis of ags i.e. biallelic or known dominant mutations, with pathogenicity assessed using our extensive mutation database / functional data, in any of trex1, rnaseh2a, rnaseh2b, rnaseh2c and samhd1 genes * a pre-defined interferon signature (consistently present, moderate or high, on at least three occasions, over a period of 6 months prior to enrolment in the study) * age ≥ 1 month and \< 18 years (either sex) * patient beneficiary or affiliated to " health insurance" * written informed consent exclusion criteria: * pre-existing disease, not due to ags, which would preclude the use of zidovudine, lamivudine and abacavir (as currently assessed in routine clinical hiv-related practice) * hla b57-01 positive result, which indicates a greater risk of abacavir hypersensitivity reaction * patients with abnormally low neutrophile counts (\<0.75 x 109/l), or abnormally low haemoglobin levels (\<7.5 g/dl or 4.65 mmol/l)(zidovudine contraindication) * positive serology for hiv, hbv * known history of cirrhosis and history of clinically relevant hepatitis within last 6 months * moderate to severe renal impairment * pregnancy, breastfeeding * patient participating to a biomedical research with drug

Keywords: aicardi-goutières syndrome reverse transcriptase inhibitors open single study interferon signature